Neurological illnesses such as stroke, epilepsy, head and spinal cord trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and many neurogenetic disorders have devastating effects on the individual and result in high social costs associated with chronic care and lost productivity. A common feature of these illnesses is neuronal loss. Many of the aforementioned disorders are related to the absence, malfunction or ineffectiveness of one gene or more and do not respond well to conventional therapeutic means. Gene transfer into the central nervous system (CNS), which involves the delivery and expression of a therapeutic gene, has, therefore, been considered as a potential approach to treatment of these disorders. This approach may mediate expression levels of neurotrophic factors, anti-apoptotic proteins, antioxidant molecules and other therapeutic factors to restore, halt or prevent neuronal degeneration. Gene therapy also offers much hope for the treatment of CNS malignancies.
The unique characteristics of the CNS, the most sophisticated organ in the body, presents several obstacles to successful gene therapy within the CNS. These characteristics include limited access to the CNS due to the physical barriers of the skull and the blood-brain barrier; the nature of terminally differentiated neurons and the difficulty of efficiently transfecting them with therapeutic genes. Moreover, the cell types found within the CNS are very diverse, many of which are critical to physiological functions and highly sensitive to any kinds of changes. This requires the development of CNS gene therapy that is restricted to a particular type of CNS cell, thus ensuring therapeutic effects in the desired cells and limiting side effects caused by gene expression in non-target CNS cells.
Specific gene expression in a selected cell type can be achieved at the level of targeted gene delivery through the use of ligand-associated delivery vectors that bind, via the ligands, to cell surface receptors that are unique to the target cells. Specific gene expression can also be achieved at the level of targeted transcription through the use of cell-specific promoters and enhancers. Cell-specific promoters are one of the primary means through which specialized cellular functions are limited to a particular differentiated cell type. The ability of these promoters to direct transcription of associated genes is regulated by the intracellular concentrations and activities of transcription factors in a specific type of cell.
Introduction of a transgene into a particular cell can sometimes result in disruption of or interference with cellular functions due to an excess of the transgene product. Due to their specificity, cell-specific promoters may give a level of transcription of a transgene that is acceptable to cellular metabolism, thus avoiding the exhaustion of protein synthesis materials and the over-accumulation of transgene products that may be toxic to transfected cells. Cell-specific promoters, because they are derived from genomic sequences, may also reduce the chance of activating host cell defense machinery and usually are less sensitive to cytokine-induced promoter inactivation than viral promoters. By using a cell-specific promoter, the stability of gene expression is expected to improve. However, the transcriptional activity of cell-specific cellular promoters is often weak, presenting a significant limitation on their use in gene therapy.